Ultrafiltration and microporous membranes are used in pressure-driven filtration processes. Practitioners in the field of separation processes by membranes easily differentiate between microporous and ultrafiltration membranes and generally distinguish between them based on their application and aspects of their structure. Microporous and ultrafiltration membranes are made, sold and used as separate and distinct products. Despite some overlap in nomenclature, they are separate entities, and are treated as such in the commercial world.
Ultrafiltration membranes are primarily used to concentrate or diafilter soluble macromolecules such as proteins, DNA, viruses, starches and natural or synthetic polymers. In the majority of uses, ultrafiltration is accomplished in the tangential flow filtration (TFF) mode, where the feed liquid is passed across the membrane surface and those molecules smaller than the pore size of the membrane pass through (filtrate) and the remaining molecules (retentate) are retained on the first side (upstream) of the membrane. As fluid also passes through there is a need to recycle or add to the retentate flow in order to maintain an efficient TFF operation. One advantage of using a TFF approach is that as the fluid constantly sweeps across the face of the membrane it tends to reduce fouling and polarization of the solutes at and near the membrane surface leading to longer life of the membrane. Ultrafiltration membranes also can be utilized in dead end filtration mode. Dead-end filtration refers to filtration where the entire fluid stream being filtered passes through the filter with no recycle or retentate flow. Whatever material doesn't pass through the filter is left on its upper (upstream) surface.
Microporous membranes are primarily used to remove particles, such as solids, bacteria, and gels, from a liquid or gas stream in dead-end filtration mode.
Ultrafiltration membranes are generally skinned asymmetric membranes, made for the most part on a support which remains a permanent part of the membrane structure. The support can be a non-woven or woven fabric, or a preformed membrane. Alternatively, a supported ultrafiltration membrane can be formed by cocasting two or more polymer solutions followed by coagulating the solution to form a multilayer membrane wherein at least one layer is an ultrafiltration membrane.
Viral removal membrane filters are increasingly being used in the biotechnology industry to provide for the safety of the therapeutic products being manufactured. These filters must remove a high proportion of any viruses that may be present while allowing most if not all of the product protein to pass through the membrane. Additionally, it is necessary that the filtration not be prematurely stopped or slowed to a uneconomically low rate of flow by plugging of the porous filter. Practitioners in the field of membrane development have found that to develop a membrane product with this desired combination of properties is indeed a challenge.
In the prior art, viral removal membranes are typically ultrafiltration membranes made to be hydrophilic and low protein binding by polymerizing a crosslinked polymeric coating on the inner porous surface and facial surfaces of the membrane. Without being limited by the following explanation, it is believed such coating processes give a randomly distributed coating thickness on the surfaces of the pores, due to the distribution of pore sizes and the stochastic nature of free radical polymerization. Since the tolerances required for an improved viral removal membrane are very strict, a method of more closely controlling coating thickness was sought.
When filtering aqueous protein solutions to remove virus therefrom with an ultrafiltration membrane, the membranes have a pore size sufficiently small to effect retention of the virus while permitting the protein to pass through the membrane. It is desirable that the membranes have high virus retention and at the same time high throughput. Virus retention is defined as Log Reduction Value (LRV), the number of times 10 must be multiplied to obtain the ratio of virus concentration in the feed to that in the filtrate. For example, a membrane with LRV of 4.0 means that it is capable of reducing viral load by a factor of 10,000 (104). Throughput is defined as volume of protein solution that can be passed through a given area of membrane before complete fouling occurs. As used herein, the term “complete fouling” refers to a condition of the membrane wherein less than 10% of the original flux of the membrane is observed when effecting filtration with the membrane to attain virus retention of an LRV of 3.5 or greater. It is generally observed that higher flux through the membrane and low protein binding of membrane surface both lead to higher throughput. Throughput values of a given membrane vary greatly depending on the type and concentration of protein used, pressure, ionic strength and other test conditions. Under typical process conditions, satisfactory ultrafiltration membranes have throughput of about 1000 L/m2 or greater.
A more representative performance gauge of a virus retentive membrane is the membrane area that is calculated according to the Vmax method. Millipore Corporation has historically used the Vmax method for determining area requirements for normal flow filtration devices (Millipore Corporation technical note AN1025EN00). This method is based upon a gradual pore plugging model that assumes membrane plugging is a result of uniform constriction of cylindrical membrane pores. The governing equation for the model istb/V=(tb/[Vmax*A]+1/[Qi*A]  (1)where                A=filtration area (m2)        V=Process Volume (L)        Vmax=Obtained from Inverse slope of a plot of t/V vs. t (L/m2)=        Qi=Initial Volumetric flow rate (L/min*mhu 2)        tb=process time (min)Equation (1) may be rearranged to estimate the filter sizing as follows:A/V=1/Vmax+1/[Qi*tb]  (2)In this equation, the contribution to sizing results from both the capacity term, (1/V max) and the flow-time term (1/(Qi,*tb)). Most biopharmaceutical applications are intermediate plugging streams; therefore both capacity and flow rate are important in sizing. This means that both the capacity term (1/V max) and the flow-time term (1/(Qi*tb)) should both be used. Ignoring the flow-time term can result in significant error in determining total filtration area required. Examples of applications in which this occurs would be in bioburden reduction steps, such as prior to a column purification step, or after a depth filtration steps. In addition, many buffer and media applications are within this Vmax range. The lower the value of A, the more desirable the membrane.        
In addition, when filtering an aqueous protein solution, the ultrafiltration membrane must be hydrophilic, that is readily wettable with water. A relevant method to assess hydrophilicity of a membrane is to measure the critical wetting surface tension (CWST) as described in U.S. Pat. No. 4,880,548, which is incorporated herein by reference. Briefly, the CWST of a porous medium may be determined by individually applying to its surface a series of liquids with varying surface tension, such as aqueous solution of aliphatic alcohol or inorganic salts, and observing the absorption or non-absorption of each liquid. The CWST of a porous medium, in units of dynes/cm, is defined as the mean value of the surface tension of the liquid which is absorbed and that of a liquid of neighboring surface tension which is not absorbed.
A further desirable characteristic of an ultrafiltration membrane used to filter protein solutions is that it be caustic stable since caustic solutions are commonly used for storage and sterilization of membrane prior to use.
It has been proposed in U.S. Pat. Nos. 4,794,002 and 5,139,881 to provide a porous ultrafiltration or microfiltration membrane formed of an inherently hydrophobic substrate such as a sulfone polymer substrate membrane, e.g. polysulfone or polyethersulfone, which is modified to have a hydrophilic surface as well as a process for making the membrane having the hydrophilic surface, wherein the hydrophilic surface is created by irreversible adsorption of a polymer with molecular weight of not less than 10,000. In one aspect of the invention, the surface of the substrate membrane is modified with a hydroxyalkyl cellulose such as hydroxypropylcellulose. In the process for making the membrane, the substrate membrane is contacted with the hydroxyalkylcellulose to effect adsorption onto or into the substrate membrane followed by removing excess non-adsorbed modifying hydroxylalkyl cellulose.
U.S. Pat. No. 6,214,382 discloses a hydrophilic membrane that is made by essentially the same process as in U.S. Pat. No. 4,794,002, only using a modifying polymer with number average molecular weight of 2,000 to 8,000.
U.S. Pat. No. 4,413,074 discloses a process for rendering hydrophilic a surface of a hydrophobic porous membrane such as a polysulfone. The hydrophobic membrane is contacted with a solution of hydroxyalkyl cellulose and a surfactant in a solvent such as water or a mixture of water and an aliphatic alcohol. The solvent then is removed from the membrane by heating under dry conditions to insolubilize the hydroxyalkyl cellulose.
It would be desirable to provide an ultrafiltration membrane capable of removing virus from protein solutions which has a high throughput in that high flux and low protein binding can be effected. Such a membrane would provide effective and economical virus removal from large batches of protein solution. In addition, it would be desirable to provide such a membrane which can be caustic sterilized without negatively affecting its throughput.